Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the α-emitting radionuclide, bismuth 213

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Abstract
We used a pretargeting technique to treat a nonobese diabetic/severe combined immunodeficient murine model of human adult T-cell leukemia with an anti-Tac antibody-streptavidin (HAT-SA) conjugate, which recognizes CD25, followed by bismuth 213 (213Bi)-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)- biotin. In the 3-step pretargeting radioimmunotherapy protocol, HAT-SA (140 or 400 μg) was administered intravenously (i.v.) to bind to the interleukin 2 receptor α (IL-2Rα; CD25)–expressing tumor cells. After 24 hours, 100 μg of a synthetic clearing agent was administered i.v. to remove unbound circulating HAT-SA conjugate from the circulation. Four hours later,213Bi–DOTA-biotin was administered i.v. for therapy. Tumor growth was significantly inhibited in 3 trials by using 250 μCi (9.25 MBq) of 213Bi–DOTA-biotin with a pretargeting technique as monitored by serum levels of soluble IL-2Rα and/or human β-2-microglobulin (P < .05, t test) and by survival of tumor-bearing mice in the treatment groups (P < .02, log rank test) as compared with the control groups. No prolongation of survival was observed with a nonspecific antibody-SA conjugate or in the absence of the radionuclide. Additionally, no prolongation of survival resulted from administration of 213Bi directly linked to intact HAT. Furthermore, there was no prolongation of survival when the β-emitting radionuclide yttrium 90 instead of the α-emitting radionuclide213Bi was used. The pretargeting approach with213Bi inhibited tumor growth more effectively than did immunotherapy with unmodified HAT. The best results were obtained with combination therapy that involved 213Bi–DOTA-biotin with a pretargeting technique supplemented by 4 weekly doses of HAT. The findings of this study support the use of this combination approach in a clinical trial in patients with IL-2Rα–expressing leukemias.

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